Understandably, providers may worry about the medication risks for the pregnant woman and her fetus/child, Byatt said, but equally important are the risks of untreated depression and anxiety. “Prenatal depression and anxiety can lead to missed obstetrical appointments, poor nutrition, poor sleep, and substance abuse,” she said. “Depression also has been associated with poor birth outcomes, including preterm birth, preeclampsia and an increased risk for delivery of a low birth weight infant.”

To assist clinicians in working with their pregnant patients, Byatt and colleagues included a Table of treatment recommendations in their article. These include using the lowest medication dose possible while avoiding undertreatment; avoiding polypharmacy; and maximizing nonmedication, evidence-based treatments.

At about the same time their literature review on antidepressant use in pregnancy was published, an article by Nulman and associates3 appeared on the neurodevelopment of children following prenatal exposure to venlafaxine (Effexor), SSRIs, or untreated maternal depression. Those investigators concluded that factors other than antide­pressant exposure during pregnancy predicted children’s intellect and behavior and that children of depressed mothers may be at risk for future psychopathology.

“You can extrapolate from the study that if you can help mom go into the postpartum period well and healthy with her symptoms in remission as much as possible, you can set the stage for mom to be in a position to care for the baby in such a way that would mitigate the child’s risk of having his or her own future mental health symptoms,” Byatt said.

Byatt was somewhat critical of a review that discussed the impact of SSRIs on fertility, pregnancy, and neonatal health.4 Domar and colleagues4 contended that there is evidence of risk with the use of SSRI antidepressants by pregnant women, that there is no evidence of improved pregnancy outcomes with SSRIs, and that pregnant women, providers, and the public should be advised of this. Byatt said that rather than conducting a systematic review of all the available evidence and coming to a nonbiased conclusion, Domar and colleagues cited a “few articles that support their conclusions,” which can worsen the stigma and confusion surrounding depression treatment during pregnancy.

SSRIs and infant death

Byatt described the recent population-based cohort study by Stephansson and colleagues2 as a “well done and very reassuring study.” Analyzing data from Denmark, Finland, Iceland, Norway, and Sweden, Stephansson and colleagues looked at the use of SSRIs during pregnancy and the risk of stillbirth and infant mortality. The large size (more than 1.6 million births) facilitated the study of rare pregnancy outcomes, such as stillbirth, neonatal death, and postneonatal death, Stephansson told Psychiatric Times.

For the study funded by the Swedish Pharmacy Company and the authors’ affiliations, the researchers obtained information on maternal use of SSRIs from prescription registries. Exposure was defined as 1 or more filled prescriptions for an SSRI from 3 months before the start of pregnancy until birth. The researchers also gathered information on maternal characteristics, pregnancy, and neonatal outcomes from patient and medical birth registries. They then estimated relative risks of still-birth, neonatal death, and postneonatal death associated with SSRI use during pregnancy, taking into account maternal characteristics and previous psychiatric hospitalizations.

Among 1,633,877 singleton births in the study from 1996 to 2007, there were 6054 stillbirths, 3609 neonatal deaths, and 1578 postneonatal deaths. A total of 29,228 mothers (1.79%) had filled a prescription for an SSRI during pregnancy.

“Women taking SSRIs had slightly increased rates of stillbirth and postneonatal death,” said Stephansson, Associate Professor at Karolinska University’s Clinical Epidemiology Unit. Women exposed to an SSRI had higher rates of stillbirth (4.62 vs 3.69 per 1000) and postneonatal death (1.38 vs 0.96 per 1000) than those who did not. The rate of neonatal death was similar between groups (2.54 vs 2.21 per 1000).

However, when the researchers considered maternal factors, there was no association with SSRIs and stillbirth or infant death rates, Stephansson said. Such factors included a history of the severity of the psychiatric disorder among women taking SSRI drugs during pregnancy, their older age, the tendency for them to be smokers, and the greater incidence of diabetes and high blood pressure.

The researchers acknowledged that they might have overestimated the actual use of antidepressants, because having a drug prescribed doesn’t always equate with using it. Stephansson noted that the study findings need confirmation by other studies in different settings. He added that the Nordic team of researchers has been looking at various issues involving SSRI use and pregnancy. Last year, in a large, multinational cohort study, Kieler and colleagues5 found the risk of PPHN “after exposure to any SSRI in late pregnancy was more than doubled.”

The results indicate that out of 11,014 mothers who used antidepressants in late pregnancy (later than gestational week 20), 33 babies (0.2%) were born with PPHN (absolute risk, 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000). With regard to SSRI use in early pregnancy, the results indicated that risk for PPHN was “slightly increased.” Specific SSRIs had sim ilar increased risks of PPHN, suggesting a class effect.

Currently, the Nordic collaboration team, according to Stephansson, is investigating sponta­neous abortions and congenital malformations and their possible association with antidepressant exposure.

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SECTION EDITORS: DEPRESSION

Marlene P. Freeman, MD is Associate Professor of Psychiatry at Harvard Medical School, Medical Director OF CTNI Director of Clinical Services, Perinatal and Reproductive Psychiatry Program at Massachusetts General Hospital in Boston.

George I. Papakostas, MD is Director of Treatment-Resistant Depression Studies in the Department of Psychiatry at Massachusetts General Hospital and Associate Professor of Psychiatry at Harvard Medical School in Boston.